We propose that both sarcopenia (loss of muscle mass) and obesity contribute to age-related immunosenescence by negatively regulating natural killer (NK) lymphocyte number and function. Preliminary studies showed an inverse correlation between body mass index and NK cell number in elderly women, but not in young adult women. Therefore, the interplay between skeletal muscle and adipose tissue may contribute to control of human NK cell development, survival, and function in the elderly. Skeletal muscle and fat are known to regulate each other via cytokines, including adipose-derived tumor necrosis factor (TNF) and IL-6, which negatively impact NK cells. Muscle produces lower levels of these cytokines, but produces abundant IL-15, which controls fat and is both absolutely required and rate-limiting for NK cell development and survival. Based on our observations we propose two hypotheses: Muscle promotes NK development and survival and fat negatively regulates NK cells. Muscle supports NK cells via IL-15 and fat inhibits NK cells via TNF and IL-6. Our novel hypotheses lead to two predictions that will be tested in the elderly. 1) NK cell number and function will correlate directly with skeletal muscle strength and mass and correlate inversely with visceral fat mass. 2) Plasma IL-15 will correlate directly with muscle strength and mass and NK cell number and function, but correlate inversely with visceral fat. Our interdisciplinary team has expertise in muscle biology, NK immunity, body composition measurement, and biostatistics. Our highly innovative work will address for the first time whether skeletal muscle affects NK cells and whether IL-15 has a role in this process. Our work will have a highly significant impact because it will open completely new areas of investigation and may suggest novel ways to treat both sarcopenia and declining immunity in aging. PUBLIC HEALTH RELEVANCE: We will investigate a new idea that muscle is good for the immune system and fat is bad for the immune system in elderly people. Specifically, we will test the effects of muscle and fat on natural killer (NK) lymphocytes that are important in fighting infections and cancer. If this idea is correct, it could open up new ways to treat fat accumulation muscle loss, and immune system weakness in old age.